The ubiquitin proteasome system (UPS) degrades the majority of proteins in mammalian cells and one of its primary functions is to selectively eliminate misfolded, potentially toxic proteins. In the UPS, protein substrates are modified by the attachment of chains of ubiquitin molecules, which target the protein for rapid degradation by the 26S proteasome. It is generally assumed that ubiquitination determines the rate of protein degradation by the UPS, but recent studies have shown that the activity of 26S proteasomes is tightly regulated and can determine rates of protein degradation in cells. Our lab and collaborators recently found that agents that raise cAMP cause the Protein Kinase A-mediated phosphorylation of the 26S subunit Rpn6 and the enhancement of multiple proteasome activities. This modification increases the capacity in cells and mouse brains to degrade misfolded, aggregation-prone proteins (e.g. mutant Tau and SOD1) that cause neurodegenerative diseases. Thus, pharmacological enhancement of proteasome function is an exciting new approach to combat various aging-associated diseases. I recently found that treatments that raise cGMP and activate Protein Kinase G also stimulate proteasome activity and protein degradation in cells. This cGMP-mediated stimulation was not due to Rpn6 phosphorylation, and therefore occurs by a different mechanism than raising cAMP. I am proposing an in-depth investigation to determine 1.) how raising cGMP stimulates proteasome function, 2.) the effect of raising cGMP on the degradation of different types of cell proteins and 3.) whether FDA-approved pharmacological agents that increase cGMP levels (e.g. PDE5 inhibitors) enhance the clearance of mutant proteins that cause Alzheimer?s Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Parkinson?s Disease. These studies should clarify the mechanisms and importance of this new mode of regulating protein degradation and its therapeutic potential.